晚期非小细胞肺癌免疫治疗：研究进展和展望
作者简介:
王婧怡（1995-），女，博士在读，主要从事胸部恶性肿瘤的精准诊疗与转化基础研究，ORCID: 0000-0001-8306-6395
邬麟: 主任医师，博士生导师，博士后合作导师，湖南省肿瘤医院/中南大学湘雅医学院附属肿瘤医院胸部内二科主任，湖南省肺癌临床研究中心主任，湖南省卫生健康高层次人才医学学科带头人。中国抗癌协会老年肿瘤专委会副主委，CSWOG常务理事，CSWOG肺癌专委会副主委兼秘书长，中华医学会肿瘤学分会肿瘤内科专委会委员，中国临床肿瘤学会（CSCO）理事，中国抗癌协会临床化疗专委会常委，中国抗癌协会原发灶不明及多原发癌专委会常委，CSCO罕见肿瘤专家委员会常委，CSCO老年肿瘤专委会常委，中国老年保健协会肺癌专委会副主委，中国医促会肿瘤肿瘤舒缓治疗学分会副主委，湖南省健康服务业协会肿瘤防治分会理事长，湖南省医师协会肿瘤医师分会副会长，湖南省抗癌协会肿瘤化疗专委会主委，湖南省抗癌协会肺癌专委会副主委，湖南省抗癌协会分子靶向治疗专委会副主委，湖南省抗癌协会肿瘤精准医学专委会副主委。从事肿瘤内科临床工作26年，专注于胸部恶性肿瘤的精准诊疗和转化基础研究，部分研究成果以第一作者/通讯作者发表于The Journal of the American Medical Association、Journal of Clinical Oncology、Lancet Oncology、Journal of Thoracic Oncology、eClinicalMedicine、Nature Communications等国外顶级SCI期刊。主编专著6本，主编/参编国内多项肺癌诊疗指南，并担任多本杂志编委和审稿人
。
通信作者:
Immunotherapy for Advanced Non-small Cell Lung Cancer: Research Progress and Perspectives
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摘要:
免疫治疗已经改变了晚期非小细胞肺癌（NSCLC）的治疗格局，在一线及后线治疗中均显现出巨大潜能。同时，随着免疫治疗的广泛应用，仍有许多问题需要进一步探讨，如疗效预测生物标志物的探索、免疫治疗模式的优化、免疫相关不良反应和特殊人群的管理等。本综述梳理了晚期NSCLC免疫治疗的研究进展，并探讨了面临的挑战和未来发展方向。
Abstract:Immunotherapy has changed the treatment landscape of advanced non-small cell lung cancer (NSCLC), showing great potential in the treatment of untreated and relapsed or refractory (R/R) patients. However, numerous issues that need further exploration remain with the wide application of immunotherapy. They include the exploration of biomarkers for efficacy prediction, the optimization of immunotherapy modalities, immune-related adverse effects, and the management of special populations. This review summarizes the progress of the research on immunotherapy for advanced NSCLC and discusses its challenges and future directions.
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Key words:
- Non-small cell lung cancer /
- Immunotherapy /
- Immune checkpoint inhibitors
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Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：王婧怡：文献调研与整理、数据整理及论文撰写钟雨玲：文献调研与整理、论文撰写邬 麟：论文构思与设计、审阅与修订
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表 1 晚期非小细胞肺癌一线ICIs单药治疗的临床试验汇总
Table 1 Summary of clinical trials of first-line ICIs monotherapy for advanced NSCLC
Study Patient Arm Primary
endpointORR (%) PFS
(months)OS (months) Updated
ORR (%)Updated PFS
(months)Updated OS
(months)KEYNOTE-024 PD-L1 TPS≥50%
advanced NSCLCPembrolizumab vs.
ChemotherapyPFS 44.8 vs. 27.8 10.3 vs.6.0;
HR=0.50NR vs. NR;
HR=0.6046.1 vs. 31.1 7.7 vs. 5.5;
HR=0.5026.3 vs. 13.4;
HR=0.62KEYNOTE-042 PD-L1 TPS≥1%
advanced NSCLCPembrolizumab vs.
ChemotherapyOS 27.0 vs. 27.0 5.4 vs. 6.5;
HR=1.0716.7 vs. 12.1;
HR=0.8127.3 vs. 26.7 5.6 vs. 6.8;
HR=1.0316.4 vs. 12.1;
HR=0.79IMpower110 PD-L1 TC≥50%/
IC≥10% advanced
NSCLCAtezolizumab vs.
ChemotherapyOS 38.3 vs. 28.6 8.1 vs. 5.0;
HR=0.6320.2 vs.13.1;
HR=0.5940.2 vs.28.6 8.2 vs. 5.0;
HR=0.5920.2 vs. 14.7;
HR=0.76EMPOWER-
Lung 1PD-L1 TPS≥50%
advanced NSCLCCemiplimab vs.
ChemotherapyOS, PFS 39 vs. 20 8.2 vs. 5.7;
HR=0.54NR vs. 14.2;
HR=0.5746.5 vs. 21.0 8.1 vs. 5.3;
HR=0.5126.1 vs. 13.3;
HR=0.57Notes: ICI: immune checkpoint inhibitor; NSCLC: non-small cell lung cancer; TPS: tumor proportion score; TC: tumor cell; IC: immune cell; ORR: objective response rate; DOR: duration of response; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; NR: not reached. 
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表 2 晚期非小细胞肺癌一线ICIs联合化疗的临床试验汇总
Table 2 Summary of clinical trials of first-line ICIs combined with chemotherapy for advanced NSCLC
Study Patient Arm Primary
endpointORR (%) PFS (months) OS (months) Updated
ORR(%)Updated PFS
(months)Updated OS
(months)KEYNOTE-189 Advanced
non-squamous
NSCLCPembrolizumab +
chemotherapy vs.
ChemotherapyOS,PFS 47.6 vs. 18.9 8.8 vs. 4.9;
HR=0.52NR vs. 11.3;
HR=0.4948.3 vs. 19.9 9.0 vs. 4.9;
HR=0.5022.0 vs. 10.6;
HR=0.60KEYNOTE-407 Advanced
squamous
NSCLCPembrolizumab +
chemotherapy vs.
ChemotherapyOS,PFS 57.9 vs. 38.4 6.4 vs 4.8;
HR=0.5615.9 vs. 11.3;
HR=0.6462.2 vs. 38.8 8.0 vs. 5.1;
HR=0.6217.2 vs. 11.6;
HR=0.71EMPOWER-
Lung 3Advanced
NSCLCCemiplima +
chemotherapy vs.
ChemotherapyOS 43.3 vs. 22.7 8.2 vs. 5.0;
HR=0.5621.9 vs. 13.0;
HR=0.7143.6 vs. 22.1 8.2 vs. 5.5;
HR=0.5521.1 vs. 12.9;
HR=0.65IMpower130 Advanced
non-squamous
NSCLCAtezolizumab +
chemotherapy vs.
ChemotherapyOS 49.2 vs. 31.9 7.0 vs. 5.5;
HR=0.6418.6 vs. 13.9;
HR=0.79CameL Advanced
non-squamous
NSCLCCamrelizumab +
chemotherapy vs.
ChemotherapyPFS 60.5 vs. 38.6 11.3 vs. 8.3;
HR=0.60NR vs. 20.9;
HR=0.7355.1 vs. 32.9 11.0 vs. 6.5;
HR=0.5527.1 vs. 19.8;
HR=0.72CameL-sq Advanced
squamous
NSCLCCamrelizumab +
chemotherapy vs.
ChemotherapyPFS 64.8 vs. 36.7 8.5 vs. 4.9;
HR=0.37NR vs. 14.5;
HR=0.5527.4 vs. 15.5;
HR=0.57ORIENT-11 Advanced
non-squamous
NSCLCSintilimab +
chemotherapy vs.
ChemotherapyPFS 51.9 vs. 29.8 8.9 vs. 5.0;
HR=0.48NR vs. NR;
HR=0.6124.2 vs. 16.8;
HR=0.65ORIENT-12 Advanced
squamous
NSCLCSintilimab +
chemotherapy vs.
ChemotherapyOS 44.7 vs. 35.4 5.5 vs. 4.9;
HR=0.54NR vs. NR;
HR=0.57RATIONALE 304 Advanced
non-squamous
NSCLCTislelizumab +
chemotherapy vs.
ChemotherapyPFS 57.4 vs. 36.9 9.7 vs. 7.6;
HR=0.65NR vs. NR 51.6 vs. 27.9 9.8 vs. 7.6;
HR=0.61RATIONALE 307 Advanced
squamous
NSCLCTislelizumab+
chemotherapy vs.
ChemotherapyPFS 72.5 vs. 49.6 7.6 vs. 5.5;
HR=0.52NR vs. NR 74.2 vs. 47.9 7.7 vs. 5.5;
HR=0.45GEMSTONE-302 Advanced
NSCLCSugemalimab+
chemotherapy vs.
ChemotherapyPFS 63.4 vs. 40.3 9.0 vs. 4.9;
HR=0.4822.8 vs. 17.7;
HR=0.67CHOICE-01 Advanced
NSCLCToripalimab +
chemotherapy vs.
ChemotherapyPFS 65.7 vs. 46.2 8.4 vs. 5.6;
HR=0.49NR vs. 17.1;
HR=0.6923.8 vs. 17.0;
HR=0.73AK105-302 Advanced
squamous
NSCLCPenpulimab +
chemotherapy vs.
ChemotherapyPFS 71.4 vs. 44.0 7.6 vs. 4.2;
HR=0.44NR vs. 19.8;
HR=0.55ASTRUM-004 Advanced
squamous
NSCLCSerplulimab +
chemotherapy vs.
ChemotherapyPFS 60.1 vs. 40.2 8.3 vs. 5.6;
HR=0.5022.7 vs.18.2;
HR=0.73
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表 3 晚期非小细胞肺癌一线ICIs联合抗血管生成治疗或双ICIs联合治疗的临床试验汇总
Table 3 Summary of clinical trials of first-line ICIs combined with antiangiogenic therapy or dual-ICIs combination therapy for advanced NSCLC
Study Patient Arm Primary
endpointORR (%) PFS
(months)OS
(months)Updated
ORR (%)Updated PFS
(months)Updated OS
(months)ICIs combined with antiangiogenic therapy IMpower150 Advanced
non-squamous
NSCLCAtezolizumab+
bevacizumab+
chemotherapy vs.
Bevacizumab+
chemotherapyOS, PFS 63.5 vs. 48.0 8.3 vs. 6.8;
HR=0.6219.2 vs. 14.7;
HR=0.788.4 vs. 6.8;
HR=0.5719.5 vs. 14.7;
HR=0.80Dual-ICIs combination therapy CheckMate 227 Advanced
NSCLCNivolumab+
ipilimumab vs.
ChemotherapyOS 33.1 vs. 27.8 5.1 vs. 5.5;
HR=0.7917.1 vs. 13.9;
HR=0.73CheckMate 9LA Advanced
NSCLCNivolumab+
ipilimumab+
chemotherapy vs.
ChemotherapyOS 38.2 vs. 24.9 6.7 vs. 5.0;
HR=0.6815.6 vs. 10.9;
HR=0.6638 vs. 25 15.8 vs. 11.0;
HR=0.74POSEIDON Advanced
NSCLCTremelimumab+
durvalumab+
chemotherapy vs.
ChemotherapyPFS 38.8 vs. 24.4 6.2 vs. 4.8;
HR=0.7214.0 vs. 11.7;
HR=0.7714.0 vs. 11.6;
HR=0.76
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表 4 晚期非小细胞肺癌二线ICIs治疗的临床试验汇总
Table 4 Summary of clinical trials of second-line ICIs for advanced NSCLC
Study Patient Arm Primary
endpointORR (%) PFS
(months)OS
(months)Updated
ORR (%)Updated PFS
(months)Updated OS
(months)KEYNOTE 010 PD-L1 TPS≥1%
previously treated
advanced NSCLCPembrolizumab
vs.
ChemotherapyOS, PFS 18 vs. 9 4.0 vs. 4.0;
HR=0.7912.7 vs. 8.5;
HR=0.6121.2 vs. 9.6 4.0 vs. 4.1;
HR=0.8411.8 vs. 8.4;
HR=0.70CheckMate 017 Previously
treated advanced
squamous NSCLCNivolumab
vs.
ChemotherapyOS 20 vs. 9 3.5 vs. 2.8;
HR=0.629.2 vs. 6.0;
HR=0.5920.0 vs. 8.8 3.5 vs. 2.6;
HR=0.619.2 vs. 6.0;
HR=0.62CheckMate 057 Previously treated
advanced
non-squamous
NSCLCNivolumab
vs.
ChemotherapyOS 19 vs. 12 2.3 vs. 4.7;
HR=0.9212.2 vs. 9.4;
HR=0.7319.5 vs. 12.4 2.3 vs. 4.4;
HR=0.9012.2 vs. 9.5;
HR=0.70OAK Previously treated
advanced NSCLCAtezolizumab
vs.
ChemotherapyOS 14 vs. 13 2.8 vs. 4.0;
HR=0.9515.7 vs. 10.3;
HR=0.74CheckMate-078 Previously treated
advanced
NSCLCNivolumab
vs.
ChemotherapyOS 16.6 vs. 4.2 2.8 vs. 2.8;
HR=0.7712.0 vs. 9.6;
HR=0.6818 vs. 4 2.8 vs. 2.8;
HR=0.7811.9 vs. 9.5;
HR=0.75RATIONALE-303 Previously
treated advanced
NSCLCTislelizumab
vs.
ChemotherapyOS 22.6 vs. 7.1 4.2 vs. 2.6;
HR=0.6316.9 vs.11.9;
HR=0.66
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